Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5]([N:7]1[CH2:11][CH:10]([OH:12])[CH:9]2[NH:13][CH2:14][CH2:15][CH:8]12)=[O:6])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:73]([C:82]([O:84][CH2:85][C:86]1[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=1)=[O:83])[C@H:74]([C:79](O)=[O:80])[C:75]([CH3:78])([CH3:77])[CH3:76]>CN1C(=O)CCC1.O>[CH2:85]([O:84][C:82](=[O:83])[NH:73][CH:74]([C:79]([N:13]1[CH2:14][CH2:15][CH:8]2[N:7]([C:5](=[O:6])[NH:4][CH:1]([CH3:3])[CH3:2])[CH2:11][CH:10]([OH:12])[CH:9]12)=[O:80])[C:75]([CH3:76])([CH3:77])[CH3:78])[C:86]1[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=1
Reactant: CC(C)NC(=O)N1CC(O)C2NCCC21
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)NC(=O)N1CC(O)C2C1CCN2C(=O)C(NC(=O)OCc1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A solution containing crude 54 (˜3.8 g, 17.9 mmol) and DIPEA (4.1 mL, 23.3 mmol) in NMP (50 mL) was cooled to 0° C. In a separate flask, Cbz-Tle-OH dicyclohexylamine salt (8.8 g, 19.7 mmol), HATU (7.5 g, 19.7 mmol), and DIPEA (4.1 mL, 23.3 mmol) were dissolved in NMP (130 mL) at 0° C. A portion of the HATU/Cbz-Tle-OH solution (117 mL, ˜1.0 equiv) was added to the solution containing 54. After 30 min, the reaction mixture was diluted with water and extracted with 1:1 Et2O/EtOAc. The combined organic extracts were washed successively with 10% H3PO4, water, saturated aqueous NaHCO3, water, and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 7.2 g of 55 as a beige-colored foam (88%, 4 steps) which was used without further purification. Mass spectrum, m/z [460.9] (M+H)+.
Reaction SMILES: C([Mg]Br)(C)C.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.COCN[C:17](=[O:27])[CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[O:27]=[C:17]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25]
Reactant: COCNC(=O)CNC(=O)OC(C)(C)C
Reactant: Brc1cccnc1
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)c1cccnc1
Reaction time: 1 h
Yield: 78 %

Procedure:
Isopropylmagnesium bromide (15.5 ml, 2M in THF) was added to a solution of 3-bromopyridine (4.92 g) in THF (30 ml) at 0° C. and stirred for 1 h. A solution of the product from step (a) (2.18 g) in THF (20 ml) was then added and the reaction mixture was stirred at room temperature for 40 h. The mixture was quenched by the addition of saturated ammonium chloride solution (250 ml) and extracted with ethyl acetate. The organic layer was washed with brine and dried (MgSO4). The solvent was evaporated off and the residue purified by chromatography (silica, 20% ethyl acetate/dichloromuethane as eluent) to give the sub-title compound (1.84 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[N:12]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][C:8]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:9][CH:10]=3)[C:5]([CH3:35])([CH3:34])[C:4]=2[CH:3]=1.[CH2:36](O)[CH3:37].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.CO>[C:8]1([C:37]2[CH:36]=[CH:33][CH:28]=[CH:29][CH:30]=2)[CH:9]=[CH:10][C:11]([N:12]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)[C:25]2[CH:24]=[CH:23][C:22]([C:19]3[CH:20]=[CH:21][C:16]4[N:12]([C:11]5[CH:10]=[CH:9][C:8]([C:28]6[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=6)=[CH:7][CH:6]=5)[C:13]5[C:4](=[CH:3][C:2]([C:15]6[CH:2]=[CH:3][CH:4]=[CH:13][CH:14]=6)=[CH:15][CH:14]=5)[C:5]([CH3:34])([CH3:35])[C:17]=4[CH:18]=3)=[CH:27][CH:26]=2)=[CH:6][CH:7]=1
Reactant: CCO
Reactant: CC1(C)c2cc(Br)ccc2N(c2ccc(-c3ccccc3)cc2)c2ccc(-c3ccccc3)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC1(C)c2cc(-c3ccccc3)ccc2N(c2ccc(-c3ccccc3)cc2)c2ccc(-c3ccc(N(c4ccc(-c5ccccc5)cc4)c4ccc(-c5ccccc5)cc4)cc3)cc21
Temperature: 72 °C
Reaction time: 8.5 h
Yield: 75 %

Procedure:
2-Bromo-10-(biphenyl-4-yl)-9,9-dimethyl-7-phenylacridan (2.5 g), bis(biphenyl-4-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboran-2-yl)phenyl]amine (3.0 g), toluene (37 ml), ethanol (9.3 ml), and a 2M potassium carbonate aqueous solution (7.2 ml) were added to a nitrogen-substituted reaction vessel and aerated with nitrogen gas for 30 min under ultrasonic irradiation. The mixture was heated after adding tetrakis(triphenylphosphine)palladium (0.11 g) and stirred at 72° C. for 8.5 hours. The mixture was allowed to cool to a room temperature, and methanol (40 ml) was added. A precipitated solid was collected by filtration and washed with water to obtain an orange crude product. The crude product was dissolved by adding toluene (360 ml), purified by adsorption using silica gel (3.6 g), and crystallized with toluene/methanol three times. Further, methanol (60 ml) was added to the product, and the product was washed and purified by heating under reflux to obtain a white powder of bis(biphenyl-4-yl)-[4-{10-(biphenyl-4-yl)-9,9-dimethyl-7-phenylacridan-2-yl}phenyl]amine (3.04 g; yield 75%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:37])[CH2:34][O:35][CH3:36])[NH:28][C:27](=[O:38])[CH2:26]2>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:37])[CH2:34][O:35][CH3:36])[NH:28][C:27](=[O:38])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Reactant: COCC(=O)Nc1cc2c(cc1F)CC(=O)N2
Product: COCC(=O)Nc1cc2c(cc1F)C(=Cc1[nH]c3c(c1C)C(=O)N(CCN1CCOCC1)CC3)C(=O)N2
Yield: 84.4 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxy-acetamide as starting materials to give N-{5-fluoro-3-[3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-methoxy-acetamide (70 mg, 84.4%) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[O:10][C@H:11]([CH3:14])[CH2:12][OH:13])[N:5]=[C:4]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:3]=1.[OH-].[Na+].Cl[C:25]([O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[O:26]>CCOC(C)=O.O>[Cl:30][C:29]([Cl:32])([Cl:31])[CH2:28][O:27][C:25](=[O:26])[NH:1][C:2]1[N:6]([C:7]2[CH:17]=[CH:16][CH:15]=[C:9]([O:10][C@H:11]([CH3:14])[CH2:12][OH:13])[CH:8]=2)[N:5]=[C:4]([C:18]([CH3:20])([CH3:19])[CH3:21])[CH:3]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: C[C@H](CO)Oc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](CO)Oc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.6 %

Procedure:
A solution of Intermediate 151b (112 mg, 0.39 mmol) in EtOAc (2.1 mL) was treated with aqueous 1N NaOH (0.7 mL, 0.70 mmol) then 2,2,2-trichloroethyl chloroformate (0.056 mL, 0.41 mmol) and the mixture was stirred at RT for 2.5 h. The mixture was treated with another portion of 2,2,2-trichloroethyl chloroformate (0.015 mL, 0.11 mmol) and stirred at RT for a further 1 h. The mixture was diluted with EtOAc and water and the phases were separated. The aqueous layer was extracted with EtOAc (×2) and the combined organic phase was washed with brine, dried (Na2SO4), and concentrated in vacuo to give a pale red gum (195 mg). The gum was purified by FCC, using 0-40% EtOAc in cyclohexane, to give the title compound as a pale golden gum (134 mg, 74%). LCMS (Method 3): Rt 4.15 min, m/z 464.2, 466.2 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[NH:11][CH:12]([CH3:14])[CH3:13].[N:15]([O-])=O.[Na+]>Cl.O>[CH:12]([N:11]1[C:3]2[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:9]=[CH:10][C:2]=2[N:1]=[N:15]1)([CH3:14])[CH3:13]
Reactant: CC(C)Nc1cc(C(=O)O)ccc1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)n1nnc2ccc(C(=O)O)cc21
Yield: 77.4 %

Procedure:
To a stirred, cold (0° C.) mixture of 4-amino-3-isopropylamino-benzoic acid (11 g) in 120 mL of 6 N hydrochloric acid was added drop-wise a solution of 5.9 g of sodium nitrite in 40 mL of water. After 2 hours the solids were collected by filtration, washed with water, and dried to give 9 grams of 3-isopropyl-3H-benzotriazole-5-carboxylic acid.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8](Cl)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[SH-:14].[Na+]>C(O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8]([SH:14])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(Cl)cnn(C(C)(C)C)c1=O
Reactant: [SH-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(S)cnn(C(C)(C)C)c1=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 96.7 %

Procedure:
To 75 ml of ethanol were added 17.0 g (0.085 mol) of 2-t-butyl-5-chloro-4-methyl-3(2H)-pyridazinone and 8.5 g (0.106 mol) of 70% sodium hydrosulfide and the mixture was stirred under reflax for 4 hours. After cooling, the mixture was poured into 300 ml of ice water and extracted with 200 ml of ethyl ether. The ether layer was washed with 100 ml of water, dried over anhydrous sodium sulfate and then freed of solvent by distillation to obtain 16.3 g of a crude product.
Reaction SMILES: [CH2:1]([N:5]1[CH2:12][CH:11]2[C:13]([CH3:15])([CH3:14])[CH:7]([CH2:8][NH:9][CH2:10]2)[CH2:6]1)[CH2:2][CH2:3][CH3:4].[NH2-].[Li+].[CH3:18][C:19]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:20]=1[CH2:21]Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH2:1]([N:5]1[CH2:6][CH:7]2[C:13]([CH3:14])([CH3:15])[CH:11]([CH2:10][N:9]([CH2:21][C:20]3[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:19]=3[CH3:18])[CH2:8]2)[CH2:12]1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(C)c(CCl)c1
Reactant: CCCCN1CC2CNCC(C1)C2(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [NH2-]
Solvent: CN(C)C=O
Product: CCCCN1CC2CN(Cc3cc(C)ccc3C)CC(C1)C2(C)C
Temperature: 60 °C
Reaction time: 4 h

Procedure:
3.5 g 3-n-butyl-9,9-dimethyl-3, 7-diazabicyclo[3,3,1]nonane were dissolved in 25 ml of dimethyl formamide, and 0.8 g of lithium amide was added to the solution. The reaction mixture was then maintained at a temperature of 60° C. for 1 hour and subsequently allowed to cool. After cooling, a solution of 5.6 g of 2,5-dimethylbenzyl chloride in 10 ml of dimethyl formamide was added dropwise, and the reaction mixture was stirred for a further 4 hours at 80° C. Then aqueous citric acid solution was added to the reaction mixture in order to dissolve the title compound as a citric acid salt. The solution was washed with diethyl ether and then rendered alkaline by adding dilute sodium hydroxide solution, whereupon the title compound was again freed as a base. The free base was extracted with diethyl ether. After the ether extract was dried over magnesium sulfate, the ether solution was filtered, and the ether was distilled off. The remaining oil was purified by distillation in a bulb tube at 210° C. and 0.01 Torr.
Reaction SMILES: C1C=[C:5]2N=N[N:9](O)[C:4]2=[CH:3]C=1.[OH2:11].C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC.[NH2:33][CH:34]1[N:40]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=2)[C:38]2[CH:47]=[CH:48][CH:49]=[CH:50][C:37]=2[N:36]([CH2:51][C:52](=[O:57])[C:53]([CH3:56])([CH3:55])[CH3:54])[C:35]1=[O:58]>C(Cl)Cl>[NH2:9][C@H:4]([C:3]([NH:33][CH:34]1[N:40]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=2)[C:38]2[CH:47]=[CH:48][CH:49]=[CH:50][C:37]=2[N:36]([CH2:51][C:52](=[O:57])[C:53]([CH3:54])([CH3:55])[CH3:56])[C:35]1=[O:58])=[O:11])[CH3:5]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)C(=O)CN1C(=O)C(N)N=C(c2ccccn2)c2ccccc21
Reactant: O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](N)C(=O)NC1N=C(c2ccccn2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
A solution of L-Boc-alanine (1.57 g, 8.33 mmol), HOBt monohydrate (1.13 g, 8.33 mmol), diisopropylethylamine (1.45 mL, 8.33 mmol) and CH2Cl2 (40 mL) was purged with nitrogen and cooled in an ice bath. To the cold solution was added 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (1.60 g, 8.33 mmol) followed by a solution of 3-amino-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one (2.92 g, 8.33 mmol) dissolved in CH2Cl2 (25 mL). The cold bath was removed and the solution stirred overnight at room temperature. The reaction mixture was extracted with H2O, 0.1 N aq. citric acid, 5% aq. NaHCO3, and brine. The remaining CH2Cl2 solution was dried (MgSO4) and concentrated to a yellow foam. The title compound was isolated via column chromatography (20% EtOAc/hexanes to 60% EtOAc/hexanes) to give 4.19 g (96% yield) of light yellow foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].O.B1(C=C)OB([CH:29]=[CH2:30])OB(C=C)O1.C1C=CN=CC=1>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:29]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=2)[CH:3]=1)=[CH2:30]
Reactant: COC(=O)c1ccc2cc(Br)ccc2c1
Reactant: C=CB1OB(C=C)OB(C=C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Solvent: COCCOC
Product: C=Cc1ccc2cc(C(=O)OC)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
Methyl 6-bromo-2-naphthalene carboxylate (98 g) was dissolved in dimethoxyethane (2 1) and tetrakis(triphenylphosphine)palladium (44 g) was added in nitrogen atmosphere. The mixture was stirred for 30 minutes at room temperature. Potassium carbonate (52 g), water (1 1) and 2,4,6-trivinylcyclotriboroxane-pyridine complex (91 g) were added and the mixture was stirred for 24 hours while refluxing with heating. There action mixture was cooled to room temperature and treated with activated alumina to obtain methyl 2-vinyl-6-naphthalene carboxylate (77 g).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.O1CC[N:21]([CH:24]=[CH:25][CH2:26][CH3:27])CC1.[NH4+].[Cl-]>CO.C(O)(=O)C>[CH2:26]([C:25]1[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:21][CH:24]=1)[CH3:27]
Reactant: CCC=CN1CCOCC1
Reactant: CCOC=C(C(=O)OCC)C(=O)C(=O)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(CC)cnc1C(=O)OCC
Temperature: 25 °C

Procedure:
To a solution of diethyl ethoxymethyleneoxalacetate (43.2 g, 0.16 mol) dissolved in CH3OH (150 mL) at -10° under N2 is added 1-morpholinobutene (25 g, 0.16 mol). The reaction is slowly warmed to room temperature over three hours, after which the CH3OH is removed in vacuo. The residue is dissolved in acetic acid (100 mL) and this solution slowly added to NH4Cl (34.2 g, 0.64 mol) dissolved in acetic acid (200 mL) at 50°-70°. The reaction is then heated to 90°-95° for two hours and 30 minutes, concentrated in vacuo, partitioned between water and the CH2Cl2, and the organic phase chromatographed over silica gel with CH2Cl2 --CH3CN (95:5) elution to give the product as an oil. Distillation at 123°-155° at 0.15 mm gives the product (23.4 g, 83% pure, 55%).
Reaction SMILES: [Li]CCCC.[F:6][C:7]([F:20])([F:19])[C:8]1[CH:9]=[C:10]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[NH2:11].C[O:22][C:23]([C:25]1([CH:39]2[CH2:42][CH2:41][CH2:40]2)[CH2:29][C:28](=[O:30])[N:27]([C:31]2[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:38])[CH2:26]1)=O.[NH4+].[Cl-]>C1COCC1>[F:6][C:7]([F:19])([F:20])[C:8]1[CH:9]=[C:10]([NH:11][C:23]([C:25]2([CH:39]3[CH2:40][CH2:41][CH2:42]3)[CH2:29][C:28](=[O:30])[N:27]([C:31]3[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:38])[CH2:26]2)=[O:22])[CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)C1(C2CCC2)CC(=O)N(c2c(C)cccc2C)C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cccc(C)c1N1CC(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(C2CCC2)CC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 1.5 %

Procedure:
n-BuLi (2.5 M solution in hexanes, 1.13 mL, 2.82 mmol) was added to a solution of 3,5-bis-trifluoromethylaniline (437 μL, 2.82 mmol) in THF (0.5 mL) at room temperature. The resulting dark brown colored solution was stirred for 10 min at room temperature. A solution of 3-cyclobutyl-1-(2,6-dimethylphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (prepared from step a, 283 mg, 0.94 mmol) in THF (3 mL) was added and stirred for 30 min at 100° C. in a sealed vial. Saturated aqueous NH4Cl solution (10 mL) was added, extracted with EtOAc (3×25 mL). The combined organic layer was washed with water (40 mL), brine (40 mL), dried (Na2SO4) and evaporated. The reaction mixture was then purified by automated flash chromatography (SiO2, 20→70% EtOAc/hexanes). Selected fractions were combined and concentrated under reduced pressure. The obtained product was further purified twice by preparative HPLC (5→90% gradient of MeCN—H2O with 0.1% TFA) to obtain the desired product 3-cyclobutyl-1-(2,6-dimethylphenyl)-5-oxo-pyrrolidine-3-carboxylic acid (3,5-bis-trifluoromethylphenyl)-amide (7 mg, 1.5% yield). LC-MS: Rt (retention time): 3.17 min, MS: (ES) m/z 499.1 (M+H+). 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 3H), 7.63 (s, 1H), 7.12-7.16 (m, 1H), 7.04-7.09 (m, 2H), 4.18 (d, 1H, J=8.5 Hz), 3.58 (d, 1H, J=8.5 Hz), 3.18 (d, 1H, J=17 Hz), 2.8 (d, 1H, J=17 Hz), 2.2 (s, 3H), 2.17 (s, 3H), 1.85-2.0 (m, 2H), 0.68-0.8 (m, 1H), 0.5-0.62 (m, 2H), 0.15-0.2 (m, 2H).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH:16]1([CH2:21][NH:22][C:23]([NH:25][CH3:26])=[S:24])[CH2:20][CH2:19][CH2:18][CH2:17]1>>[BrH:1].[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2([OH:4])[CH2:2][S:24][C:23](=[N:22][CH2:21][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[N:25]2[CH3:26])=[CH:6][C:7]=1[S:12](=[O:15])(=[O:14])[NH2:13]
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Reactant: CNC(=S)NCC1CCCC1
Product: Br
Product: CN1C(=NCC2CCCC2)SCC1(O)c1ccc(Cl)c(S(N)(=O)=O)c1

Procedure:
4.7 g of 2-bromo-4'-chloro-3'-sulfamoylacetophenone were reacted with 2.6 g of 1-cyclopentylmethyl-3-methylthiourea according to the prescription given in Example 23 and the colorless crystalline final product was filtered off. Melting point: 189° C. (decomposition).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[C-:27]#[N:28].[K+]>>[C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:27]#[N:28])[CH:2]=1
Reactant: [C-]#N
Reactant: C1COCCN1
Reactant: Cc1cccc(C=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Product: Cc1cccc(C(C#N)N2CCOCC2)c1

Procedure:
As in Example 35, the following reactions are carried out. m-Tolualdehyde is reacted with p-toluenesulfonic acid, morpholine and KCN to give α-(m-tolyl)-4-morpholineacetonitrile as crystals, m.p. 59°-60° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2([CH3:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:3]=1.Cl[C:17]([O:19][CH3:20])=[O:18]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:17](=[O:18])([O:19][CH3:20])[O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:9]1([CH3:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)Cl
Reactant: CC1(c2cc(F)ccc2O)CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)Oc1ccc(F)cc1C1(C)CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To a solution of 4-fluoro-2-(1-methylcyclohexyl)phenol (23.5 g, 113 mmol), TEA (31 mL, 226 mmol) and DMAP (700 mg, 5.7 mmol) in CH2Cl2(250 mL) was added methyl chloroformate dropwise at 0° C. The mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was poured onto crushed ice and extracted with CH2Cl2(100 mL×3). The organic layer was washed with brine, dried over MgSO4, evaporated under vacuum. The crude product was purified by chromatography on silica gel diluted with (hexane:ethyl acetate=100:1) to give 4-fluoro-2-(1-methylcyclohexyl)phenyl methyl carbonate as red brown oil (43.9 g, 72.1% yield). 1H NMR (400 MHz, CDCl3) δ 7.10 (dd, J=3.2, 11.2 Hz, 1H), 7.05-7.02 (m, 1H), 6.93-6.88 (m, 1H), 3.91 (s, 3H), 2.02-1.96 (m, 2H), 1.66-1.36 (m, 8H), 1.23 (s, 3H).
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].N1C=[CH:15][N:14]=[N:13]1.[C:17](#[N:19])C>>[N:14]1([CH:2]([CH3:11])[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[CH:15]=[N:19][CH:17]=[N:13]1
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: c1c[nH]nn1
Reactant: CC#N
Product: CC(C(=O)c1ccccc1)n1cncn1
Yield: 55 %

Procedure:
To a solution of 223 g (1 mol) of 2-bromopropiophenone in 300 ml of acetonitrile is added dropwise to a boiling mixture of 414 g (6 mols) of triazole and 1,200 ml of acetonitrile, and the mixture is heated at the boil for 8 hours. Thereafter, the mixture is evaporated down in vacuo, the residue is taken up in 750 ml of dichloromethane and 750 ml of water, and the organic phase is washed with several 500 ml portions of water and dried over anhydrous sodium sulphate. After the solvent has been distilled off, the remaining residue is distilled in vacuo. 111 g (55% of theory) of 2-(1,2,4-triazol-1-yl)-propiophenone of boiling point 133° C./0.15 mbar and of melting point 117° C. are obtained. ##STR21##
Reaction SMILES: Cl[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][C:19]=2[O:30][CH3:31])=[N:15][N:14]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:31][O:30][C:19]1[CH:20]=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:22]=[CH:23][C:18]=1[C:16]1[O:17][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[N:14][N:15]=1
Reactant: COc1cc(N2CCOCC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2Cl)o1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N2CCOCC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2N2CCOCC2)o1
Yield: 90 %

Procedure:
As described for example 106, 4-{4-[5-(5-chloro-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-3-methoxy-phenyl}-morpholine (100 mg, 0.23 mmol) using morpholine instead of dimethylamine hydrochloride and potassium carbonate was converted to the title compound (100 mg, 90%) which was obtained as an off-white solid. MS: m/e=490.3 [M+H]+.